The hippocampus is one of two major areas in the brain that maintains a supply of proliferating cells that are able to produce new neurons well into adulthood. Here, self-renewing stem and transient-amplifying progenitor cells in the subgranular zone (SGZ) of the hippocampal dentate gyrus (DG) divide, migrate a short distance, and differentiate into new granule cell neurons that integrate into the existing circuitry of the brain. Although it is thought the new neurons generated may participate in learning and memory, the factors that regulate stem/progenitor cell migration, proliferation, differentiation, and eventual synaptic integration into the brain are not well understood. The EphB1 and EphB2 receptor tyrosine kinases are expressed in hippocampal stem/progenitor cells during embryonic and postnatal development as well as in the adult brain. In vivo studies using gene targeted mice show that deletion of EphB1 and more profoundly EphB1+EphB2 results in a reduced number of nestin-positive stem/progenitor cells that populate the developing DG. Mutant stem/progenitor cells that do manage to populate the DG exhibit defective polarity of cell processes, ectopic positioning of cell bodies outside of the normal SGZ niche, and increased proliferation. Our data leads to the hypothesis that, upon interaction with their cognate ephrin-B transmembrane ligands, the EphB receptors transduce important signals into hippocampal stem/progenitor cells to control their migration during development as the DG forms and later during adulthood as the SGZ continues to give rise to newborn neurons. To further test our ideas we will: (1) determine the intracellular signaling mechanisms that EphB receptors use to control the migration of stem/progenitor cells during development of the hippocampus, and (2) use conditional strategies to delete EphB receptors in stem/progenitor cells of the mature hippocampus in order to determine how these molecules may regulate neuroblast behaviors specifically in the adult brain. The proposed research will provide a better general understanding of stem cell biology and the cell-cell interactions and biochemical signals that are at play. It is further anticipated that this work will lead to advances in our understanding of the signaling mechanisms that regulate neurogenesis in the normal brain. This may provide important insight into the molecular basis behind our ability to learn and store memories. Finally, as damage to the hippocampus and associated changes in stem cell proliferation/migration can result from numerous pathologies, the proposed research may also provide novel molecular targets for future stem cell therapies to treat individuals suffering from neurological diseases, degeneration, or injury. PUBLIC HEALTH RELEVANCE: The hippocampus is a major center of the brain involved in learning and memory and is one of the two areas in the adult brain that contain stem cells. The studies proposed focus on Eph receptor tyrosine kinases which are expressed on hippocampal stem cells and function to transduce chemical signals that are important for normal stem cell migration and proliferation patterns. It is anticipated this research will lead to advances in our understanding of the molecular regulation of stem cells in the developing and adult brain, and may provide insight into how we learn and store memories. Furthermore, as damage to the hippocampus can lead to changes in stem cell proliferation, the proposed research may also provide novel molecular targets for future stem cell therapies to treat individuals suffering from neurological diseases, degeneration, or injury.